sb-243213 and Necrosis

Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Blood-Brain Barrier; Cell Line; Conditioning, Operant; Feeding Behavior; Humans; Indoles; Isoindoles; Male; Mice; Necrosis; Parietal Cells, Gastric; Pyrazines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Agonists; Stereoisomerism; Weight Gain